Airborne PCBs are those that have higher vapor pressures, lower chlorination, and should be substrates for metabolic activation. We hypothesize that the lower halogenated biphenyls are activated by hepatic enzymes to oxygenated species that are electrophilic and bind to proteins and DNA. Our preliminary data indeed show that PCBs are metabolized to electrophiles and free radicals that bind to cellular targets and that the metabolism of PCBs produces reactive oxygen species, resulting in DNA strand breaks and 8- oxodeoxyguanosine formation in DNA and that a quinone/semiquinone may be a/the major metabolite involved in these effects. Employing the Solt-Farber initiation-selection protocol, we also identified several lower chlorinated biphenyls as initiators of hepatocarcinogenesis in the rat. We therefore propose to extend our studies to: 1) determine the initiating potential of airborne, semi-volatile PCBs and to analyze the structural and metabolic requirements needed for carcinogenic potency, 2) analyze for oncogene mutations and karyoptypic changes during PCB carcinogenesis in the Solt-Farber experiments, 3) investigate the types of genotypic damage induced by PCBs and their metabolites in vitro, in cells in culture, and in vivo, 4) examine the ease of formation and the reactivity of PCB-derived semiquinone radicals, and 5) determine the biologic effects and the influence of Route of Exposure (IP vs. inhalation) of airborne PCBs (a typical "air mixture" of PCBs, or single PCB congeners, or hydroxy-PCBs) on specific changes in expression of xenobiotic-metabolizing enzymes, antioxidant enzymes or redox indicators in the rat. Jointly these studies may explain why some PCBs are activated to genotoxins, while others are not, which target genes are involved, the nature of the DNA lesions, and the mutations that ensue. These data may also provide clues about whether nutritional or other interventions are warranted to protect highlyexposed humans. These mechanistic and susceptibility issues will form a basis for the quantitative human health risk assessment for these important Superfund Chemicals, arising from multiple sources.